Nine returning characters from previous Crash titles star in the home console version of Crash: Mind over Mutant. The protagonist of the game, Crash Bandicoot, is a bandicoot who must defeat the main antagonist Doctor Cortex and free the Titans from the control of Cortex's new device. Aiding Crash is Aku Aku, an ancient wooden mask who can take control of Titans by entering their heads. Crash's genius sister, Coco Bandicoot, appears initially as a boss character under the control of Cortex's and Brio's handheld device. Afterward, she acts as a playable character during the co-operative mode of the Wii and Xbox 360 console versions; she is replaced by a white-furred version of Crash named \"Carbon Crash\" in the PlayStation 2 version. Crunch Bandicoot, Crash's muscular cyborg friend, also appears in the game as a brainwashed boss.
Crash: Mind over Mutant takes place a year later after the events of where Crash of the Titans left off. The Titans, free from the control of Doctor Neo Cortex, have spread throughout the Wumpa Islands and cultivated their own societies and towns. All seems well until a rejuvenated Cortex teams up with his old partner Nitrus Brio to invent a personal digital assistant, the \"NV\", that can control the minds of both mutants and bandicoots by transmitting bad Mojo, forcefully siphoned from Cortex's former boss Uka Uka. Crash and Aku Aku are not affected by the device, meanwhile N. Gin launches an attack on the bandicoots. Crash and Aku Aku defeated him, but they discover their family members Coco and Crunch are soon transformed into monstrous version of themselves who seek Crash's destruction.
The bandicoots also receive these helmets, though Crash and Aku Aku are unimpressed (Crash's malfunctions, and Aku Aku's doesn't fit). Coco and Crunch are obsessed, however, and before long the devices turn them into slavering beasts. Crash and Aku Aku must travel to various locales and settlements across Wumpa Island to save Coco, Crunch, and the various mutants they encounter along the way. They must also track down old enemies that Cortex has either betrayed or abandoned (N. Gin, Nina, Uka Uka) and piece together the story of the NV's creation.
Eventually, they discover the source of the helmets in Cortex's space station, and there confront the doctor himself. Using N. Brio's mutagen, Cortex transforms himself into a mutant to fight Crash one-on-one, but is defeated when Crash jacks him and initiates the station's self-destruct. Cortex escapes in an escape pod, leaving Crash and Aku Aku stranded. The ship crash-lands on Wumpa Island. Miraculously, the two survive. They happily reunite with Crunch and Coco, and decide not to clean up any of the mess that's now piled up in their front yard.
All is good until Cortex has rejuvenated at which point he finds himself unable to leave things at peace. Teaming up with his old partner, Doctor Nitrus Brio, Cortex invents a PDA (Personal Digital Assitant) called the 'NV', which transmits bad mojo, extracted from Cortex's old boss Uka-Uka, in order to control the minds of both mutants and Bandicoots alike. 1e1e36bf2d